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PDBsum entry 5ugt
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Oxidoreductase
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PDB id
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5ugt
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References listed in PDB file
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Key reference
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Title
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Evaluating the contribution of transition-State destabilization to changes in the residence time of triazole-Based inha inhibitors.
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Authors
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L.A.Spagnuolo,
S.Eltschkner,
W.Yu,
F.Daryaee,
S.Davoodi,
S.E.Knudson,
E.K.Allen,
J.Merino,
A.Pschibul,
B.Moree,
N.Thivalapill,
J.J.Truglio,
J.Salafsky,
R.A.Slayden,
C.Kisker,
P.J.Tonge.
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Ref.
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J Am Chem Soc, 2017,
139,
3417-3429.
[DOI no: ]
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PubMed id
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Abstract
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A critical goal of lead compound selection and optimization is to maximize
target engagement while minimizing off-target binding. Since target engagement
is a function of both the thermodynamics and kinetics of drug-target
interactions, it follows that the structures of both the ground states and
transition states on the binding reaction coordinate are needed to rationally
modulate the lifetime of the drug-target complex. Previously, we predicted the
structure of the rate-limiting transition state that controlled the
time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the
discovery of a triazole-containing diphenyl ether with an increased residence
time on InhA due to transition-state destabilization rather than ground-state
stabilization. In the present work, we evaluate the inhibition of InhA by 14
triazole-based diphenyl ethers and use a combination of enzyme kinetics and
X-ray crystallography to generate a structure-kinetic relationship for
time-dependent binding. We show that the triazole motif slows the rate of
formation for the final drug-target complex by up to 3 orders of magnitude. In
addition, we identify a novel inhibitor with a residence time on InhA of 220
min, which is 3.5-fold longer than that of the INH-NAD adduct formed by the
tuberculosis drug, isoniazid. This study provides a clear example in which the
lifetime of the drug-target complex is controlled by interactions in the
transition state for inhibitor binding rather than the ground state of the
enzyme-inhibitor complex, and demonstrates the important role that on-rates can
play in drug-target residence time.
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